Plasticity and metaplasticity are hallmark features of the neural system controlling breathing. Respiratory plasticity is a persistent change in breathing control following transient stimuli. Metaplasticity is a change in the capacity to express plasticiy (plastic plasticity). One well-studied model of respiratory plasticity is phrenic long- term facilitation (pLTF), a persistent increase in phrenic motor output following exposure to moderate acute intermittent hypoxia (AIH). Preconditioning with repetitive acute intermittent hypoxia (rAIH) or chronic intermittent hypoxia (CIH) enhances pLTF, demonstrating a degree of respiratory metaplasticity. Multiple cellular mechanisms give rise to phenotypically similar long-lasting phrenic motor facilitation (pMF), including the so-called Q and S pathways to pMF. These pathways are named for the G proteins initiating plasticity. For example, moderate AIH-induced pLTF requires Gq-coupled 5-HT2 receptor activation, protein kinase C (PKC) activity, new synthesis of brain derived neurotrophic factor (BDNF) and downstream signaling via TrkB and ERK MAP kinases. Conversely, stimulation of Gs coupled 5-HT7 receptors activates cAMP, inducing new synthesis of an immature TrkB isoform and downstream protein kinase B/Akt activation. Normally, the Q and S pathways interact via mutual (cross-talk) inhibition. Thus, in normal rats, the dominant Q pathway to pLTF is constrained by sub-threshold S pathway activation (eg. by 5-HT7 receptor activation). The fundamental hypothesis guiding this proposal is that rAIH preconditioning elicits pLTF metaplasticity by reducing cross-talk inhibition between the S and Q pathways to pMF, thereby enhancing pLTF following moderate AIH by enabling independent contributions from both pathways. Thus, we predict that rAIH-enhanced pLTF (ie. metaplasticity) results from independent contributions from both 5-HT2 and 5-HT7 receptor activation. This research is significant from a biological perspective since it advances our understanding of basic mechanisms giving rise to respiratory motor plasticity and meta-plasticity. It is significant from a clinical perspective since rAIH has considerable therapeutic potential in debilitating clinical disorders that compromise respiratory and non-respiratory motor function.